Cholesterol ester hydrolase inhibitors

ABSTRACT

The compounds of the formula: ##STR1## in which R 1  is alkyl of 4 or more carbon atoms, cycloalkyl, 1-adamantyl, 2-adamantyl, 3-noradamantyl, 3-methyl-1-adamantyl, 1-fluorenyl, 9-fluorenyl, cycloalkylalkyl, phenyl, substituted phenyl, alkyl, alkoxy, halo, nitro, cyano or trifluoromethyl, phenylalkyl or substituted phenylalkyl, where the substituent on the benzene ring is alkyl, alkoxy, halo, nitro, cyano, trifluoromethyl or phenyl; R 2  is hydrogen, alkyl or R 1  taken with R 2  and the nitrogen atom to which they are attached form a heterocyclic moiety of the formula: ##STR2## wherein ##STR3## in which R 7  is hydrogen, alkyl, hydroxy, alkanoyloxy, hydroxyalkyl, hydroxycarbonyl, alkoxycarbonyl, phenyl or substituted phenyl, in which the substituent is alkyl, alkoxy, halo, nitro, cyano, haloalkyl, perhaloalkyl or dialkylaminoalkyl; R 8  is hydrogen or alkyl or R 7  and R 8  taken together are polymethylene; R 9  is hydrogen, alkyl, phenyl or substituted phenyl, in which the substituent is alkyl, alkoxy, halo, nitro, cyano or perhaloalkyl; R 10  is hydrogen, alkyl or gemdialkyl; n is one of the integers 0, 1 or 2; and R 3 , R 4 , R5 and R 6  are, independently, hydrogen, alkyl, alkoxy, halo, nitro, cyano or perhaloalkyl, alkoxycarbonyl or hydroxycarbonyl; and when X is --NR 9  -- or R 7  is an amino alkyl group, a pharmaceutically acceptable salt thereof; useful as inhibitors of cholesterol ester hydrolase.

This is a continuation of Ser. No. 07/771,580, filed Oct. 4, 1991, nowabandoned, which is a continuation of Ser. No. 07/594,241, filed Oct. 9,1990, now abandoned, which is a continuation-in-part of Ser. No.07/436,841, filed Nov. 15, 1989, now abandoned.

BACKGROUND OF THE INVENTION

Full absorption of dietary cholesterol into the bloodstream is dependentupon cholesterol esterase (cholesterol ester hydrolase; CEH) activity.Bhat et al., Biochem. Biophys. Res. Commun. 109 486 (1982); Gallo et al.J. Lipid Research 25 604 (1984). The removal of cholesterol esterasefrom pancreatic juice results in an eighty percent reduction in absorbedcholesterol. By inhibiting the action of cholesterol esterase, serumcholesterol levels can be beneficially controlled.

Hosie et at., J. Biological Chem. 262 260 (1987) discusses theirreversible inhibition of cholesterol esterase by p-nitrophenyl N-alkylcarbamates and the reversible inhibition of cholesterol esterase bycholesterol-N-alkyl carbamates.

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a group of novelcarbamate esters which are cholesterol ester hydrolase inhibitors. Thecompounds of this invention present the structural formula: ##STR4## inwhich

R¹ is branched or straight chain, saturated or unsaturated alkyl of 4 to20 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, 1-adamantyl,2-adamantyl, 3-noradamantyl, 3-methyl-1-adamantyl, 1-fluorenyl,9-fluorenyl, cycloalkylalkyl where the cycloalkyl moiety has 3 to 8carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, phenyl,substituted phenyl where the substituents are alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano ortrifluoromethyl, phenylalkyl of 7 to 26 carbon atoms or substitutedphenylalkyl, where the alkyl moiety is 1 to 20 carbon atoms and thesubstituent on the benzene ring is alkyl of 1 to 6 carbon atoms, alkoxyof 1 to 6 carbon atoms, halo, nitro, cyano, trifluoromethyl or phenyl;

R² is hydrogen, alkyl of 1 to 6 carbon atoms or R¹ taken with R² and thenitrogen atom to which they are attached form a heterocyclic moiety ofthe formula: ##STR5## wherein ##STR6## in which

R⁷ is hydrogen, branched or straight chain alkyl of 1 to 6 carbon atoms,hydroxy, alkanoyloxy of 2 to 6 carbon atoms, hydroxyalkyl of 1 to 6carbon atoms, hydroxycarbonyl, alkoxycarbonyl of 2 to 16 carbon atoms,phenyl or substituted phenyl in which the substituent is alkyl of 1 to 6carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano,haloalkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms ordialkylaminoalkyl in which each alkyl group contains from 1 to 6 carbonatoms;

R⁸ is hydrogen or branched or straight chain alkyl of 1 to 6 carbonatoms or R⁷ and R⁸ taken together are polymethylene of 2 to 6 carbonatoms;

R⁹ is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or substitutedphenyl in which the substituent is alkyl of 1 to 6 carbon atoms, alkoxyof 1 to 6 carbon atoms, halo, nitro, cyano or perhaloalkyl of 1 to 6carbon atoms;

R10 is hydrogen, alkyl of 1 to 6 carbon atoms or gemdialkyl of 2 to 12carbon atoms;

n is one of the integers 0, 1 or 2;

and

R³, R⁴, R⁵ and R⁶ are, independently, hydrogen, branched or straightchain alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo,nitro, cyano or perhaloalkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 2to 16 carbon atoms or hydroxycarbonyl;

and when X is --NR⁹ -- or R⁷ is an amino alkyl group, a pharmaceuticallyacceptable salt thereof.

The preferred compounds of this invention, based upon their in vitrocholesterol esterase inhibitory properties, are those of the formula:##STR7## in which

R¹ is branched or straight chain alkyl of 4 to 20 carbon atoms,cycloalkyl of 4, 5, 6 or 7 carbon atoms, cycloalkylalkyl of 6 to 8carbon atoms, phenylalkyl of 7 to 26 carbon atoms;

R² is hydrogen, methyl, ethyl or R¹ and R² taken together with thenitrogen atom to which they are attached form a heterocyclic moiety ofthe formula: ##STR8## wherein ##STR9## in which

R⁷ is hydrogen, branched or straight chain alkyl of 1 to 6 carbon atoms,

hydroxy, hydroxyalkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6carbon atoms, hydroxycarbonyl, alkoxycarbonyl of 2 to 6 carbon atoms,phenyl or substituted phenyl in which the substituent is alkyl o#1 to 6carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano,haloalkyl of 1 to 6 carbon atoms or perhaloalkyl of 1 to 6 carbon atoms;

R⁸ is hydrogen or branched or straight chain alkyl of 1 to 6 carbonatoms or R⁷ and R⁸ taken together are polymethylene of 2 to 6 carbonatoms;

R¹⁰ is hydrogen, alkyl of 1 to 6 carbon atoms or gemdialkyl of 2 to 12carbon atoms;

n is one of the integers 0, 1 or 2;

and

R³, R⁴, R⁵ and R⁶ are, independently, hydrogen, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, nitro, halo, alkoxycarbonyl of 2to 16 carbon atoms, hydroxycarbonyl, cyano or trihalomethyl.

In the description of the compounds of this invention, by halo,applicants mean chloro, bromo, iodo or fluoro. The perhaloalkylsubstituents are preferably perfluoroalkyl and the alkyl and alkoxysubstituents preferably have from 1 to 4 carbon atoms.

The novel carbamate esters provided by the present invention can beprepared by the following process in which the symbol R¹¹ will be usedto represent a group having the formula A. ##STR10##

The present invention provides a process for the preparation of acarbamate ester having the formula R¹ R² N--CO--O--R¹¹ where R¹, R² andR¹¹ are as defined above or a pharmaceutically acceptable salt thereof,wherein:

(a) a phenol having the formula R¹¹ OH, where R¹¹ is as defined above,is reacted with a carbamoylating agent to introduce a carbamoyl grouphaving the formula R¹ R² N--CO-- at the phenolic oxygen atom wherein R¹and R² are as defined above subject to the proviso that where X is --CR⁸(OH)-- or --NH-- in the carbamate ester, the alcoholic oxygen atom oramine nitrogen atom of X in the carbamoylating agent may be protectedagainst carbamoylation with a removable protecting group; or

(b) an amine having the formula R¹ R² NH, where R¹ and R² are as definedin respect of the carbamate ester except that, where X represents --CR⁸(OH)-- or --NH-- in the carbamate ester, then the alcoholic oxygen atomor the amine nitrogen atom of X may be protected againstphenoxycarbonylation by protection with a removable protecting group, isreacted with a phenoxycarbonylating agent for introducing a substitutedphenoxycarbonyl group having the formula --CO--OR¹¹ where R¹¹ is asdefined above; and, if appropriate, a removable protecting group isremoved and, if desired, a free base form of the carbamate ester where Xis --NR⁹ -- may be converted into a pharmaceutically acceptable acidaddition salt thereof by addition of an acid.

The carbamoylation of a phenol may be carried out in a solvent such asmethylene chloride. A tertiary amine, for example, triethylamine, may beincluded in the reaction mixture as a catalyst. As carbamoylating agentthere is preferably used an isocyanate having the formula R¹ -NCO whereR¹ is as defined above. In this case, R² is hydrogen in the carbamateester obtained as product. ##STR11##

As an alternative to the isocyanate, a carbamoyl halide of the formulaR¹ R² N--CO--Hal where R¹ and R² are as defined above and Hal ishalogen, preferably chlorine, may be employed as carbamoylating agent.

The isocyanate reactant may be prepared by reacting a primary aminehaving the formula R¹ NH₂ where R¹ is as defined above with phosgene. Asubstantial excess

    R.sup.1 NH.sub.2 +COCl.sub.2 →R.sup.1 --NCO+2HCl

of the amine should normally be avoided since it may lead to theformation of a urea derivative (R¹ --NH--)₂ CO as by-product. Thereaction of the primary amine R¹ NH₂ with phosgene may yield theN-monosubstituted carbamoyl chloride R¹ HN--COCl but, if so, thisproduct tends to be unstable and to dissociate into the isocyanate R¹--NCO and hydrogen chloride. The N,N-disubstituted carbamoyl chlorides,i.e. the compounds R¹ R² N--CO--Hal where R² is other than hydrogen, canbe prepared by reacting a secondary amine R¹ R² NH with phosgene.

The carbamate ester of the present invention may also be prepared byphenoxycarbonylation of a primary or secondary amine R¹ R² NH. Asphenoxycarbonylating agent there is preferably used the chloroformateester of the appropriate phenol. The chloroformam ester can be preparedby reacting the phenol R¹¹ OH with phosgene or by reaction withtrichloromethyl chloroformate.

    R.sup.11 OH+CCl.sub.3 --O--CO--Cl→R.sup.11 --O--CO--Cl

    R.sup.11 --O--CO--Cl+R.sup.2 R.sup.2 NH→R.sup.11 --O--CO--NR.sup.1 R.sup.2

Where it is intended to prepare an end compound in which the symbol Xrepresents --CR⁸ (OH)-- or --NH--, protection of the alcoholic hydroxylgroup or the amine nitrogen atom of X is advisable to prevent undesiredreaction at the wrong location. The books entitled "Protective Groups InOrganic Chemistry", J. F. W. McOmie (ed.), Plenum Press, London and NewYork (1973) and "Protective Groups in Organic Synthesis", T. W. Greene,John Wiley & Sons, New York (1981) provide many examples of protectinggroups that may be used. Of course, the protecting group should be soselected that it can be removed from the phenoxycarbonylation productor. carbamoylation product under conditions in which the carbamate esterdesired as end compound can survive. In particular, it should be notedthat the carbamate esters may react with nucleophiles under basicconditions and thus such reaction conditions are best avoided forremoving the protecting group. As an example of a synthesis, secondaryamines having the formula B or C ##STR12## may be aryloxycarbonylatedwith a chloroformate ester of an appropriate p-phenoxyphenol and theresultant carbamates having the formula D or E ##STR13## are convertedinto the compounds F or G by hydrolysis during work up of the reactionmixture. ##STR14##

The novel carbamates of the present invention where R¹ and R² includes--NR⁹ -- as X are basic compounds which can be convened intopharmaceutically acceptable acid addition salts by addition of an acid.The salt may be derived from such organic and inorganic acids as lactic,acetic, citric, tartaric, succinic, maleic, fumaric, malonic, gluconic,hydrochloric, hydrobromic, phosphoric, nitric, sulphuric andmethanesulphonic and similarly known acceptable acids.

The invention also provides a pharmaceutical composition comprising anew carbamate ester according to the invention or a pharmaceuticallyacceptable salt thereof in association or combination with apharmaceutically acceptable carrier and a method of making such acomposition by bringing the carbamate ester or its pharmaceuticallyacceptable salt into association or combination with the carrier.

EXAMPLE 1 Butylcarbamic acid 4-phenoxyphenyl ester

Triethylamine (15 ml, 0.11 mol) was added dropwise under a nitrogenatmosphere to a solution of 4-phenoxyphenol (25.1 g, 0.14 mol) and butylisocyanate (18 ml, 0.16 mol) in 400 ml of methylene chloride. After theaddition, the solution was stirred overnight at room temperature. Thesolution was extracted with 1 N HCl, dried (MgSO₄) and the solventremoved under reduced pressure to give 39.59 g of a tan solid.Recrystallization from diisopropyl ether gave the title compound as awhite crystalline solid (21.01 g, 55%), mp 75°-77° C.

Elemental analysis for C₁₇ H₁₉ NO₃ Calc'd: C, 71.56; H, 6.71; N, 4.91Found: C, 71.78; H, 6.80; N, 5.06

EXAMPLE 2 1-Piperidinecarboxylic acid 4-phenoxyphenyl ester

A solution of 4-phenoxyphenol (5.0 g, 26.9 mmol) and dimethylaniline(3.4 ml, 26.8 mmol) in 35 ml of benzene plus 1.5 ml of dioxane was addeddropwise over 15 minutes under a nitrogen atmosphere to a solution oftrichloromethyl chloroformate (1.6 ml, 13.3 mmol) in 30 ml of benzene atice bath temperature. After the addition, the cooling bath was removedand the stirring continued for 24 hours. The reaction was cooled to icebath temperature and a solution of piperidine (2.7 ml, 27.3 mmol) andpyridine (4.4 ml, 54.4 mmol) in 20 ml of benzene was added dropwise over15 minutes. After the addition, the reaction was stirred at ice bathtemperature for 3 hours. The cooling bath was removed and the stirringcontinued for 22 hours. The reaction was diluted with benzene andextracted two times with 1 N HCl. The organic solution was dried overanhydrous MgSO₄ and the solvent was removed under reduced pressure togive 7.21 g of an oil. Purification by HPLC (hexane:EtOAc) gave 5.05 gof a light yellow crystalline solid. Recrystallization from diisopropylether gave the title compound as a white crystalline solid (3.11 g,39%), mp 74°-76° C.

Elemental analysis for C₁₈ H₁₉ NO₃ Calc'd: C, 72.71; H, 6.44; N, 4.71Found: C, 72.40; H, 6.42; N, 4.78

EXAMPLE 3 (4-Phenylbutyl)carbamic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (3.11 g, 33%), mp 104°-105° C.

Elemental analysis for C₂₃ H₂₃ NO₃ Calc'd: C, 76.43; H, 6.41; N, 3.88Found: C, 76.13; H, 6.28; N, 3.88

EXAMPLE 4 (1,5-Dimethylhexyl)carbamic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (4.0 g, 44%), mp 64°-65° C.

Elemental analysis for C₂₁ H₂₇ NO₃ Calc'd: C, 73.87; H, 7.97; N, 4.10Found: C, 74.19; H, 7.77; N, 3.85

EXAMPLE 5 4-Phenyl1-piperidinecarboxylic acid 4-phenoxyphenl ester

In the same manner as described in Example 2, the title compound wasproduced as white crystalline solid (4.20 g, 42%), mp 122°-124° C.

Elemental analysis for C₂₄ H₂₃ NO₃ Calc'd: C, 77.19; H, 6.21; N, 3.75Found: C, 77.04; H, 6.17; N, 4.12

EXAMPLE 6 4-Phenyl-1-piperazinecarboxylic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (4.68 g, 47%), mp 159°-161° C.

Elemental analysis for C₂₃ H₂₂ N₂ O₃ Calc'd: C, 73.78; H, 5.92; N, 7.48Found: C, 73.47: H, 5.85; N, 7.37

EXAMPLE 7 4-Morpholinecarboxylic acid 4-phenoxyphenol ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (4.07 g, 51% ), mp 95°-96° C.

Elemental analysis for C₁₇ H₁₇ NO₄ Calc'd: C, 68.22; H, 5.72; N, 4.68Found: C, 67.96; H, 5.93; N, 4.63

EXAMPLE 8 4-Methyl-1-piperidinecarboxylic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (3.88 g, 46%), mp 47°-49° C.

Elemental analysis for C₁₉ H₂₁ NO₃ Calc'd: C, 73.29; H, 6.80; N, 4.50Found: C, 73.40; H, 7.09; N, 4.53

EXAMPLE 9 4-Methyl-1-piperazinecarboxylic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, with the exception thatupon extracting with 1N HC1 an emulsion formed which was broken bybasifying with 5% NaHCO₃. After further work-up, as described in Example2, the title compound was produced as a white crystalline solid (5.21 g,62%), mp 79°-81° C.

Elemental analysis for C₁₈ H₂₀ N₂ O₃ Calc'd: C, 69.21; H, 6.45; N, 8.97Found: C, 69.11; H, 6.79; N, 8.84

EXAMPLE 10 4-Thiomorpholinecarboxylic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (5.01 g, 59%), mp 101°-103° C.

Elemental analysis for C₁₇ H₁₇ NO₃ S Calc'd: C, 64.74; H, 5.43; N, 4.44Found: C, 64.96; H, 5.46; N, 4.50

EXAMPLE 11 Octylcarbamic acid 4phenoxyphenyl ester

In the same manner as described in Example 1, the title compound wasproduced as a white crystalline solid after purification by columnchromatography (silica gel, 230-400 mesh) using 8:1 hexane: ethylacetate as an eluent (8.10 g, 88%), mp 44°-46° C.

Elemental analysis for C₂₁ H₂₇ NO₃ Calc'd: C, 73.87; H, 7.97; N, 4.10Found: C, 73.90; H, 8.01; N, 4.19

EXAMPLE 12 1-Pyrrolidinecarboxylic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (4.43 g, 58%), mp 53°-55° C.

Elemental analysis for C₁₇ H₁₇ NO₃ Calc'd: C, 72.07; H, 6.05; N, 4.94Found: C, 71.97; H, 6.30; N, 4.77

EXAMPLE 13 Cyclohexylcarbamic acid 4-phenoxyphenyl ester

In the same manner as described in Example 1, the title compound wasproduced as a white crystalline solid after recrystallization of thecrude reaction product from isopropanol (7.51 g, 90% ), mp 166°-168° C.

Elemental analysis for C₁₉ H₂₁ NO₃ Calc'd: C, 73.29; H, 6.80; N, 4.50Found: C, 73.18; H, 6.94; N, 4.48

EXAMPLE 14 Cyclohexylmethylcarbamic acid 4phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (3.49 g, 40%), mp 100°-102° C.

Elemental analysis for C₂₀ H₂₃ NO₃ Calc'd: C, 73.82; H, 7.12; N, 4.30Found: C, 73.79; H, 7.12; N, 4.29

EXAMPLE 15 Tricyclo[3,3,1,1(3.7)dec-1-yl-carbamic acid 4-phenoxyphenylester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (1.54 g, 16%), mp 145°-147° C.

Elemental analysis for C₂₃ H₂₅ NO₃ Calc'd: C, 76.01; H, 6.93; N, 3.85Found: C, 76.08; H, 6.91; N, 3.83

EXAMPLE 16 (1,1,3,3-Tetramethylbutyl)carbamic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (2.0 g, 22%), mp 70°-71 ° C.

Elemental analysis for C₂₁ H₂₇ NO₃ Calc'd: C, 73.87; H, 7.97; N, 4.10Found: C, 73.80; H, 7.94; N, 4.10

EXAMPLE 17 (1-Ethylpentyl)carbamic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (2.87 g, 33%), mp 70°-72° C.

Elemental analysis for C₂₀ H₂₅ NO₃ Calc'd: C, 73.37; H, 7.70; N, 4.28Found: C, 73.30; H, 7.67; N, 4.24

EXAMPLE 18 (1,3-Dimethylbutyl)carbamic acid 4phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (5.03 g, 60%), mp 71°-74° C.

Elemental analysis for C₁₉ H₂₃ NO₃ Calc'd: C, 72.82; H, 7.40; N, 4.47Found: C, 72.78; H, 7.45; N, 4.39

EXAMPLE 19 Butylcarbamic acid 4-(4-methylphenoxy)phenyl ester

A mixture of p-cresol (41.8 ml, 0.4 mol) and sodium methoxide (21.2 g,0.4 mol) in 400 ml of anhydrous pyridine was refluxed with stirringunder nitrogen for 1 hour. The methanol was distilled off. After coolingto room temperature 4-bromoanisole (49.1 ml, 0.4 mol) and copper (I)chloride (6 g, 0.06 mol) were added and the mixture refluxed for 17hours. Most of the pyridine was removed by distillation. The residue waspoured into water, acidified with dilute HCl (1:1 conc. HCl:H₂ O) andextracted with methylene chloride. The organic layer was extracted twotimes with 1 N NaOH, dried (MgSO₄) and the solvent removed under reducedpressure to give a brown solid. Purification by HPLC (hexane-methylenechloride) gave 4methoxy-4'-methyldiphenyl ether as a light tancrystalline solid (73.47 g, 88%), mp 39°-44° C.

Elemental analysis for C₁₄ H₁₄ O₂ Calc'd: C, 78.48; H, 6.59 Found: C,78.22; H, 6.67

4-Methoxy-4'-methyl-diphenyl ether (25 g, 0.12 mol) was dissolved in 120ml of glacial acetic acid and then treated with 100 ml of 48% HBr. Themixture was heated to reflux during which time everything dissolved. Theresulting solution was refluxed for 4.5 hours. The reaction mixture waspoured into ice water and extracted three times with methylene chloride.The combined organic extracts were washed five times with water, dried(MgSO₄) and the solvent removed under reduced pressure to give a brownsolid. Purification by HPLC (hexane-methylene chloride) gave4-hydroxy-4'-methyldiphenyl ether as an off-white crystalline solid(19.50 g, 83%), mp 74°-76° C.

Elemental analysis for C₁₃ H₁₂ O₂ Calc'd: C, 77.98; H, 6.04 Found: C,78.31; H, 6.13

In the same manner as described in Example 1, the title compound wasproduced from the intermediate prepared in the preceding paragraph as awhite crystalline solid after recrystallization of the crude reactionproduct from hexanediisopropyl ether (4.99 g, 67%), mp 64°-66° C.

Elemental analysis for C₁₈ H₂₁ NO₃ Calc'd: C, 72.22; H, 7.07; N, 4.68Found: C, 72.61; H, 7.13; N, 4.79

EXAMPLE 20 Butylcarbamic acid 4-(4-nitrophenoxy)phenyl ester

4-Methoxyphenol (25 g, 0.20 mol) was heated under a nitrogen atmosphereto 70° C. during which time the solid melted. Eighty-five percentpotassium hydroxide (12.4 g, 0.19 mol) was added all at once and themixture stirred at 70° C. for 1 hour. 1-Bromo-4-nitrobenzene (33 g, 0.16mol) and copper powder (0.1 g, 1.57 mmol) were added and the mixturestirred at 190° C. for 3 hours. After cooling to room temperature, theresidue was partitioned between benzene and water. The organic layer wasthen extracted two times with 5% KOH, dried (MgSO₄) and the solventremoved under reduced pressure to give a brown solid. Purification byHPLC (hexane-methylene chloride) gave 4-methoxy-4'-nitrodiphenyl etheras a yellow crystalline solid (19.05 g, 49%), mp 107°-109° C.

Elemental analysis for C₁₃ H₁₁ NO₄ Calc'd: C, 63.67; H, 4.52; N, 5.71Found: C, 64.00; H, 4.43; N, 5.85

A suspension of 4-methoxy-4'-nitrodiphenyl ether (5.0 g, 20.4 mmol) in25 ml of glacial acetic acid plus 20 ml of 48% HBr was heated under anitrogen atmosphere to reflux temperature. During this time, everythingdissolved. The solution was then. refluxed for 3 hours. Upon cooling toroom temperature, crystals formed. The crystals were collected byfiltration, washed with water and dried under high vacuum to give4-hydroxy-4'-nitrodiphenyl ether as a yellow crystalline solid (4.34,92%), mp 168°-172° C.

Elemental analysis for C₁₂ H₉ NO₄ Calc'd: C, 62.34; H, 3.92; N, 6.06Found: C, 62.01; H, 3.93; N, 6.09

In the same manner as described in Example 1, the title compound wasproduced from the intermediate prepared in the preceding paragraph as alight yellow crystalline solid after recrystallization of the crudereaction product from methylene chloride-diisopropyl ether (3.49 g,71%), mp 122°-124° C.

Elemental analysis for C₁₇ H₁₈ N₂ O₅ Calc'd: C, 61.81; H, 5.49; N, 8.48Found: C, 61.57; H, 5.45; N, 8.29

EXAMPLE 21 Butylcarbamic acid 4-(4-chlorophenoxy)phenyl ester

A mixture of 4-bromoanisole (35 ml, 0.28 mol), 4-chlorophenol (43 g,0.33 mol), anhydrous K₂ CO₃ (13 g, 0.09 mol) and copper bronze (0.38 g,5.98 mmol) were stirred under a nitrogen atmosphere at 210° C. for 2hours. After cooling to room temperature, the mixture was dissolved inmethylene chloride, extracted two times with 1 N NaOH, dried (MgSO₄) andthe solvent removed under reduced pressure to give a brown liquid.Excess 4-bromoanisole was removed by distillation under reduced pressure(60°-73° C., 1 mm) and the residual crystalline solid was purified byHPLC (hexane-methylene chloride). 4-Methoxy-4'-chlorodiphenyl ether wasisolated as a white crystalline solid (28.84 g, 44%), mp 49°-51° C.

Elemental analysis for C₁₃ H₁₁ ClO₂ Calc'd: C, 66.53; H, 4.73 Found: C,66.66; H, 4.82

In the same manner described in the second paragraph of Example 19,4-hydroxy-4'-chlorodiphenyl ether was produced as a white crystallinesolid (16.92 g, 90% ), mp 69°-71° C.

Elemental analysis for C ₁₂ H₉ ClO₂ Calc'd: C, 65.32; H, 4.11 Found: C,65.18; H, 4.16

In the same manner as described in Example 1, the title compound wasproduced from the intermediate of the preceding paragraph as a whitecrystalline solid after recrystallization of the crude reaction productfrom diisopropyl ether (4.18 g, 72%), mp 106°-108° C.

Elemental analysis for C₁₇ H₁₈ ClNO₃ Calc'd: C, 63.85; H, 5.67; N, 4.38Found: C, 63.78; H, 5.78; N, 4.41

EXAMPLE 22 Butylcarbamic acid 2,6-dimethyl-4-(4-methylphenoxy)phenylester

In the same manner as described in paragraphs 1 and 2 of Example 19,4-methoxy-3,4', 5-trimethyldiphenyl ether was produced as a light yellowoil (23.8 g, 82%). Demethylation gave 4-hydroxy-3,4',5-trimethyldiphenyl ether as a white crystalline solid (4.31 g, 46%)after purification by HPLC (methylene:hexane) and recrystallization fromhexane, mp 58°-60° C.

Elemental analysis for C₁₅ H₁₆ O₂ Calc'd: C, 78.92; H, 7.06 Found: C,78.79; H, 7.28

In the same manner as described in Example 1, the title compound wasproduced from the intermediate prepared in the preceding paragraph as awhite crystalline solid after recrystallization of the crude reactionproduct from diisopropyl ether (3.91 g, 78%), mp 110°-112° C.

Elemental analysis for C₂₀ H₂₅ NO₃ Calc'd: C, 73.37; H, 7.70; N, 4.28Found: C, 73.06; H, 7.83; N, 4.32

EXAMPLE 23 4-Methyl-1-piperidinecarboxylic acid4-(4-methylphenoxy)phenyl ester

In the same manner as described in Example 2, the title compound wasproduced from the intermediate prepared in paragraphs 1 and 2 of Example19 as a white crystalline solid after recrystallization from diisopropylether (1.78 g, 22%), mp 79°-81° C.

Elemental analysis for C₂₀ H₂₃ NO₃ Calc'd: C, 73.82; H, 7.12; N, 4.30Found: C, 73.78; H, 7.06; N, 4.25

EXAMPLE 24 (1,5-Dimethylhexyl)carbamic acid 4-(4-methylphenoxy)phenylester

In the same manner as described in Example 2, the title compound wasproduced from the intermediate prepared in paragraphs 1 and 2 of Example19 as a white crystalline solid after recrystallization from hexane(5.16 g, 58%), mp 45°-47° C.

Elemental analysis for C₂₂ H₂₉ NO₃ Calc'd: C, 74.33; H, 8.22; N, 3.94Found: C, 74.11; H, 8.28; N, 3.84

EXAMPLE 25 4-Methyl-1-piperidinecarboxylic acid4-(4-chlorophenoxy)phenyl ester

In the same manner as described in Example 2, the title compound wasproduced from the intermediate prepared in paragraphs 1 and 2 of Example21 as a white crystalline solid after recrystallization from hexane(3.83 g, 54%), mp 72°-75° C.

Elemental analysis for C₁₉ H₂₀ ClNO₃ Calc'd: C, 65.99; H, 5.83; N, 4.05Found: C, 65.91; H, 5.86; N, 4.08

EXAMPLE 26 (1-Methylhexyl)carbamic acid 4-phenoxy)phenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid after recrystallization fromhexane (5.38 g, 62%), mp 59°-61° C.

Elemental analysis for C₂₀ H₂₅ NO₃ Calc'd: C, 73.37; H, 7.70; N, 4.28Found: C, 73.28; H, 7.66; N, 4.37

EXAMPLE 27 (1,5-Dimethylhexyl)carbamic acid 4-(4-chlorophenoxy)phenylester

In the same manner as described in Example 2, the title compound wasproduced from the intermediate prepared in paragraphs 1 and 2 of Example21 as a white crystalline solid after recrystallization from hexane(4.54 g, 60%), mp 46°-48° C.

Elemental analysis for C₂₁ H₂₆ ClNO₃ Calc'd: C, 67.10; H, 6.97; N, 3.73Found: C, 67.02; H, 6.94; N, 3.58

EXAMPLE 28 Butylcarbamic acid 2-fluoro-4-phenoxyphenyl ester

A solution of 85% potassium hydroxide (3.88 g, 58.8 mmol) in 3 ml ofwater was added to a solution of phenol (6.1 g, 64.8 mmol) in 40 ml oftoluene. The resulting mixture was refluxed under a nitrogen atmosphereand a Dean-Stark trap for 3.5 hours. After standing overnight at roomtemperature, the toluene was removed by distillation under reducedpressure and the resulting solid dried under high vacuum. To this solid4-bromo-2-fluoroanisole (6.4 ml, 49.6 mmol) and copper (1) chloride (0.1g, 1.0 mmol) were added and the mixture heated at 180° C. for 2 hours.After cooling to room temperature, the mixture was partitioned betweendiethyl ether and water and extracted. The ether layer was extracted twotimes with 1N NaOH, dried (MgSO₄) and the solvent was removed underreduced pressure to give 9.73 g of a brown oil. Purification of thematerial by column chromatography (silica gel, 230-400 mesh) usinghexane-methylene chloride as the eluent gave 3-fluoro-4-methoxydiphenylether as a clear oil (8.56 g, 79%): IR(film) 3080, 3020, 2970, 2940,2850, 1595, 1510 and 1490 cm⁻¹ ; ms m/e, 218 (m.sup. +).

In the same manner as described in the second paragraph of Example 19,3-fluoro-4-hydroxydiphenyl ether was produced as an oil (6.57 g, 92%):ms m/e, 204 (m⁺).

Elemental analysis for C ₁₂ H₉ FO₂ Calc'd: C, 70.58; H, 4.44 Found: C,70.24; H, 4.33

In the same manner as described in Example 1, the title compound wasproduced from the intermediate of the preceding paragraph as an oilafter purification by column chromatography (silica gel, 230-400 mesh)using hexane-methylene chloride as an eluent (5.76 g, 97%): ms m/e, 303(m⁺).

Elemental analysis for C₁₇ H₁₈ FNO₃ Calc'd: C, 67.32; H, 5.98; N, 4.62Found: C, 66.94; H, 5.93; N, 4.51

EXAMPLE 29 Butylcarbamic acid 4-(4-methoxyphenoxy)phenyl ester

In the same manner as described in paragraph 1 of Example 19,4-benzyloxy-4'-methoxydiphenyl ether was produced as a white crystallinesolid after trituration with hexane of the HPLC (eluent:hexane-methylene chloride) purified material (24.53 g, 64%), mp106°-108° C.

Elemental analysis for C₂₀ H₁₈ O₃ Calc'd: C, 78.41; H, 5.92 Found: C,78.29; H, 5.90

4-Benzyloxy-4'-methoxydiphenyl ether was dissolved in 150 ml of ethylacetate. To this solution, 2 g of 10% Pd-C was added and the mixturehydrogenated at room temperature and 25 psi for 24 hours. After removalof the catalyst by filtration through celite and removal of the solventunder reduced pressure, 5.63 g of a crystalline solid remained.Recrystallization of this material from diisopropyl etherhexane produced4-hydroxy-4'-methoxydiphenyl ether as a white crystalline solid (4.74 g,84%), mp 88°-90° C.

Elemental analysis for C₁₃ H₁₂ O₃ Calc'd: C, 72.21; H, 5.59 Found: C,72.12; H, 5.29

In the same manner as described in Example 1, the title compound wasproduced from the intermediate of the preceding paragraph as a whitecrystalline solid after recrystallization of the crude reaction productfrom diisopropyl ether (3.85 g, 88%), mp 63°-64° C.

Elemental analysis for C₁₈ H₂₁ NO₄ Calc'd: C, 68.55; H, 6.71; N, 4.44Found: C, 68.51; H, 6.58; N, 4.52

EXAMPLE 30 4-Methyl-1-piperidinecarboxylic acid4-(4-methoxyphenoxy)phenyl ester

In the same manner as described in Example 2, the title compound wasproduced from the intermediate prepared in paragraphs 1 and 2 of Example29 as a white crystalline solid after recrystallization from diisopropylether (3.34 g, 74%), mp 81°-84° C.

Elemental analysis for C₂₀ H₂₃ NO₄ Calc'd: C, 70.36; H, 6.79; N, 4.10Found: C, 70.33; H, 6.73; N, 3.70

EXAMPLE 31 (1,5-Dimethylhexyl)carbamic acid 4-(4-methoxyphenoxy)phenylester

In the same manner as described in Example 2, the title compound wasproduced from the intermediate prepared in paragraphs 1 and 2 of Example29 as a white crystalline solid after recrystallization from hexane(0.83 g, 12%), mp 64°-65° C.

Elemental analysis for C₂₂ H₂₉ NO₄ Calc'd: C, 71.13; H, 7.87; N, 3.77Found: C, 71.14; H, 8.14; N. 3.77

EXAMPLE 32 Butylcarbamic acid 4 -[4-(1,1-dimethylethyl)phenoxy]phenylester

In the same manner as described in paragraphs 1 and 2 of Example 19,4-(1,1-dimethylether)-4'-methoxydiphenyl ether was produced as a lightyellow oil (55.95 g, 86%). Demethylation gave4-(1,1-dimethylether)-4'-methoxydiphenyl ether as a light yellow oil(8.09 g, 68%): IR (film) 3380, 3050, 2970, 2910, 2880, 1605 and 1500cm⁻¹ ; ms m/e, 242 (m⁺).

In the same manner as described in Example 1, the title compound wasproduced from the intermediate in the preceding paragraph as a whitecrystalline solid after recrystallization of the crude reaction productfrom hexane (3.62 g, 74%), mp 78°-80° C.

Elemental analysis for C₂₁ H₂₇ NO₃ Calc'd: C, 73.87; H, 7.97; N, 4.10Found: C, 73.58; H, 7.90; N, 4.08

EXAMPLE 33 Butylcarbamic acid 2-bromo-4-phenoxyphenyl ester

Bromine (21.0 g, 0.13 mol) was added dropwise under a nitrogenatmosphere over 3 hours to an ice cold solution of 4-phenoxyphenyl (25.0g, 0.13 mol) in 125 ml of carbon disulfide. After the addition, thereaction was stirred at ice bath temperature for 1 hour. The coolingbath was removed and the stirring continued at room temperatureovernight. The solvent was removed under reduced pressure. The residualoil was taken up in methylene chloride and the organic solution waswashed with brine, dried (MgSO₄) and the solvent was removed underreduced pressure to give 37.2 g of a light brown oil. Purification ofthis material on HPLC using methylene. chloride as an eluent gave2-bromo-4-phenoxyphenol as a light yellow oil (29.7 g, 85%): IR (film)3500, 3050, 3020, 1580 and 1470 cm⁻¹ ; ms m/e, 264/266 (m⁺).

In the same manner as described in Example 1, the title compound wasproduced from the intermediate of the preceding paragraph as a whitecrystalline solid after recrystallization of the crude reaction productfrom diisopropyl ether (4.35 g, 63%), mp 57°-60° C.

Elemental analysis for C ₁₇ H₁₈ BrNO₃ Calc'd: C, 56.06; H, 4.98; N, 3.84Found: C, 55.68; H, 5.01; N, 3.79

EXAMPLE 34 4-Methyl1-piperidinecarboxylic acid 2-bromo-4-phenoxyphenylester

In the same manner as described in Example 2, the title compound wasproduced from the intermediate prepared in paragraph 1 of Example 32 asa white crystalline solid after recrystallization from hexane (5.71 g,65%), mp 65°-68° C.

Elemental analysis for C₁₉ H₂₀ BrNO₃ Calc'd: C, 58.47; H, 5.16; N, 3.59Found: C, 58.23; H, 5.05; N, 3.38

EXAMPLE 35 (1,5-Dimethylhexyl)carbamic acid 2-bromo-4-phenoxyphenylester

In the same manner as described in Example 2, the title compound wasproduced from the intermediate prepared in paragraph 1 of Example 32 asa white crystalline solid after recrystallization from hexane (4.26 g,45%), mp 64°-67° C.

Elemental analysis for C₂₁ H₂₆ BrNO₃ Calc'd: C, 60.00; H, 6.23; N, 3.33Found: C, 60.06; H, 6.08; N, 3.31

EXAMPLE 36 Hexylcarbamic acid 4-phenoxyphenyl ester

In the same manner as described in Example 1, the title compound wasformed in high yield. Recrystallization of the crude reaction mixturefrom diisopropyl ether gave 2.18 g (26%) of the title compound as awhite crystalline solid, mp 57°-59° C.

Elemental analysis for C₁₉ H₂₃ NO₃ Calc'd: C, 72.82; H, 7.40; N, 4.47Found: C, 72.68; H, 7.17; N, 4.81

EXAMPLE 37 (1,5-Dimethylhexyl)carbamic acid 2-fluoro-4-phenoxyphenylester

In the same manner as described in Example 2, the title compound wasproduced from the intermediate prepared in paragraphs 1 and 2 of Example28 as a white, waxy solid after recrystallization from hexane (6.40 g,73%), mp 37°-41° C.

Elemental analysis for C₂₁ H₂₆ FNO₃ Calc'd: C, 70.17; H, 7.29; N, 3.90Found: C, 70.16; H, 7.17; N, 3.71

EXAMPLE 38 4,4-Dimethyl-1piperidinecarboxylic acid 4-phenoxyphenol ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (4.1 g, 45%), mp 63°-65° C.

Elemental analysis for C₂₀ H₂₃ NO₃ Calc'd: C, 73.82; H, 7.12; N, 4.30Found: C, 73.86; H, 7.23; N, 4.36

EXAMPLE 39 3-Methyl-1-piperidinecarboxylic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (2.20 g, 26%), mp 41°-43° C.

Elemental analysis for C₁₉ H₂₁ NO₃ Calc'd: C, 73.29; H, 6.80; N, 4.50Found: C, 73.16; H, 6.66; N, 4.24

EXAMPLE 40 Hexahydro-1H-azepine-1-carboxylic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (4.09 g, 49%), mp 75°-77° C.

Elemental analysis for C₁₉ H₂₁ NO₃ Calc'd: C, 73.29; H, 6.80; N, 4.50Found: C, 72.97; H, 6.72; N, 4.52

EXAMPLE 41 4-Methyl-1-piperidinecarboxylic acid 2-fluoro-4-phenoxyphenylester

In the same manner as described in Example 2, the title compound wasproduced from the intermediate prepared in paragraphs 1 and 2 of Example28 as a crystalline solid (3.18 g, 39%), mp 43°-46° C.

Elemental analysis for C₁₉ H₂₀ FNO₃ Calc'd: C, 69.29; H, 6.12; N, 4.25Found: C, 69.50; H, 6.23; N, 4.26

EXAMPLE 42 4-Ethyl-1-piperidinecarboxylic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (4.76 g, 55%), mp 38°-40° C.

Elemental analysis for C₂₀ H₂₃ NO₃ Calc'd: C, 73.82; H, 7.12; N, 4.30Found: C, 74.09; H, 7.20; N, 4.33

EXAMPLE 43 1,4-Piperidinedicarboxylic acid 4-ethyl-1-(4phenoxyphenyl)diester

In the same manner as described in Example 2, the title compound wasproduced as a clear oil (7.18 g, 73%), FAB, MS, m/e 370 (M+H).

Elemental analysis for C₂₁ H₂₃ NO₅ Calc'd: C, 68.28; H, 6.28; N, 3.79Found: C, 67.67; H, 6.30; N, 4.01

EXAMPLE 44 4-Hydroxy1-piperidinecarboxylic acid 4-phenoxyphenyl ester

A solution of 4-phenoxyphenol (30 g, 0.16 mol) and dimethylaniline (20.4ml, 0.16 mol) in 200 ml of benzene plus 9 ml of dioxane was addeddropwise over 15 minutes under a nitrogen atmosphere to a solution oftrichloromethyl chloroformate (9.7 ml, 0.08 mol) in 60 ml of benzene atice bath temperature. After the addition, the cooling bath was removedand the stirring continued for 24 hours. The reaction mixture wasfiltered and the filtrate was then added dropwise under a nitrogenatmosphere to a solution of 4-hydroxypiperidine (16.3 g, 0.16 mol) andpyridine (26.1 ml, 0.32 mol) in 150 ml each of benzene, methylenechloride and THF at ice bath temperature. After the addition, thereaction was stirred at ice bath temperature for 3 hours. The coolingbath was removed and the stirring continued overnight. The reactionmixture was diluted with benzene and washed with 1N HCl. The organicsolution was separated, dried over anhydrous MgSO4 and the solventremoved under reduced pressure to give 46.4 g of a yellow mushy solid.Purification by HPLC (hexane:EtOAc) gave 13.3 g of a white solid.Recrystallization from diisopropyl ethermethanol gave the title compoundas a white crystalline solid (10.4 g, 21%), mp 128°-130° C.

Elemental analysis for C₁₈ H₁₉ NO₄ Calc'd: C, 69.00; H, 6.11; N, 4.47Found: C, 68.99; H, 6.06; N, 4.43

EXAMPLE 45 4Propyl-1-piperidinecarboxylic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (1.86 g, 21%), mp 68°-70° C.

Elemental analysis for C₂₁ H₂₅ NO₃ Calc'd: C, 74.31; H, 7.42; N, 4.13Found: C, 74.45; H, 7.44; N, 4.24

EXAMPLE 46 1.4-Piperidinedicarboxylic acid 1-(1-phenoxyphenyl ester)

The material prepared in Example 43 (3.0 g, 8.1 mmol) was dissolved in50 ml of THF plus 25 ml of water. One equivalent of 1N NaOH was addedand the reaction mixture was stirred under a nitrogen atmosphere at roomtemperature for 24 hours. The THF was removed under reduced pressure.The residue was partitioned between ethyl acetate and water. The aqueouslayer was washed two additional times with ethyl acetate. The aqueouslayer was acidified with 1N HCl and the product extracted with ethylacetate. The ethyl acetate solution was dried (anhydrous MgSO₄) and thesolvent removed under reduced pressure to give 2.34 g of a white solid.Recrystallization from diisopropyl ether-methanol gave the titlecompound as a white crystalline solid (0.79 g, 28%), mp 140°-141° C.

Elemental analysis for C₁₉ H₁₉ NO₅ Calc'd: C, 66.85; H, 5.61; N, 4.10Found: C, 66.82; H, 5.61; N, 4.18

EXAMPLE 47 3,3-Dimethyl-1-piperidinecarboxylic acid 4-phenoxyphenylester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (2.59 g, 29%), mp 57°-60° C.

Elemental analysis for C₂₀ H₂₃ NO₃ Calc'd: C, 73.82; H, 7.12; N, 4.30Found: C, 73.66; H, 7.11; N, 4.36

EXAMPLE 48 4-(Acetyloxy)-1-piperidinecarboxylic acid 4-phenoxyphenylester

The material prepared in Example 44 (2.0 g, 6.38 mmol) was dissolved 40ml of methylene chloride. Potassium carbonate (8.8 g, 63.8 mmol) andacetyl chloride (9.1 ml, 128 mmol) were added and the mixture wasstirred under nitrogen atmosphere at room temperature overnight. Thereaction mixture was washed with water. The organic solution was thenseparated, dried (anhydrous MgSO₄) and the solvent removed under reducedpressure to give 2.22 g of a white solid. Recrystallization from hexanegave the title compound as a white crystalline solid (1.68 g, 74%), mp99°-101° C.

Elemental analysis for C₂₀ H₂₁ NO₅ Calc'd: C, 67.59; H, 5.96; N, 3.94Found: C, 67.74; H, 5.95; N, 4.22

EXAMPLE 49 4-Methyl-1-piperidinecarboxylic acid2-(methoxycarbonyl)-4-phenoxyphenyl ester

A solution of bromine (42 g, 0.26 mol) in 50 ml of carbon disulfide wasadded under a nitrogen atmosphere over 6 hours to a solution of4-phenoxyphenol (50 g, 0.27 mol) in 400 ml of carbon disulfide atapproximately -5° C. After the addition, the reaction was stirred atapproximately 3° C. for 3 hours and then at room temperature for 12hours. The solvent was removed under reduced pressure. The residue wasdissolved in methylene chloride and washed with brine. The organicsolution was separated, dried (anhydrous MgSO₄) and the solvent removedunder reduced pressure to give a light brown oil. To remove theunreacted 4-phenoxyphenol, the material was subjected to HPLC(hexane-methylene chloride). NMR analysis of the isolated material(single spot on TLC) showed it to be a mixture of mono and dibrominatedphenols. Distillation of this mixture then gave 2-bromo-4-phenoxyphenolas a clear liquid (44.35 g, 64%), bp 137°-143° C. (2 mm).

Elemental analysis for C₁₂ H₉ BrO₂ Calc'd: C, 54.37; H, 3.42 Found: C,54.12; H, 3.33

n-Butyl lithium (59 ml of a 1.6 M solution in hexanes, 94.4 mmol) wasadded dropwise over 30 minutes under a nitrogen atmosphere to a solutionof 2-bromo-4-phenoxyphenol (10.0 g, 37.7 mmol) in 50 ml of dry THF at-78° C. After the addition, the solution was stirred at -78° C. for 1hour. An excess of CO₂ was then added through a tube of Drierire® intothe reaction mixture. After the addition, the cooling bath was removedand the stirring continued for 1 hour. The reaction was quenched with 1NHCl. Most of the THF was removed under reduced pressure. The residue waspartitioned between 1N HCl and EtOAc. The organic layer was separated,dried (anhydrous MgSO₄) and the solvent removed under reduced pressureto give 9.81 g of a light yellow solid. This solid was dissolved in CH₂Cl₂ containing a small amount of methanol and the solution extractedwith 5% NaHCO₃. The organic layer was separated and the aqueous layerextracted two additional times with methylene chloride. The aqueouslayer was acidified with 1N HCl and the desired product extracted withmethylene chloride. The methylene chloride solution was dried (anhydrousMgSO₄) and the solvent removed under reduced pressure to give2-hydroxy-5-phenoxybenzoic acid as a light yellow solid (7.05 g, 81%),mp 126°-128° C.

Elemental analysis for C₁₃ H₁₀ O₄ Calc'd: C, 67.82; H, 4.38 Found: C,67.86; H, 4.52

An excess of diazomethane in diethyl ether was added in portions to asolution of 2-hydroxy-5-phenoxybenzoic acid (3.53 g, 15.3 mmol) in 50 mlof methylene chloride. The reaction was monitored by TLC. When all ofthe acid had been consumed, the reaction mixture was quenched withglacial acetic acid. The reaction mixture was then partitioned with 1NHCl. The organic layer was separated, washed with 5% NaHCO₃, dried(anhydrous MgSO₄) and the solvent removed under reduced pressure to give4.08 g of a light brown oil. Purification of this oil on silica gel(230-400 mesh) using hexane-methylene chloride as the eluent gave2-hydroxy-5-phenoxybenzoic acid methyl ester as a white crystallinesolid (3.27 g, 87%), mp 33°-35° C.

Elemental analysis for C₁₄ H₁₂ O₄ Calc'd: C, 68.85; H, 4.95 Found: C,68.66; H, 4.97

Sodium hydride (0.38 g, 9.93 mmol of a 60% oil dispersion) was added inportions under a nitrogen atmosphere to a solution of2-hydroxy-5-phenoxybenzoic acid methyl ester (2.0 g, 8.19 mmol) in 30 mlof benzene. The reaction was stirred at room temperature for 30 minutes.4-Methyl-1-piperidinecarbonyl chloride (1.46 g, 9.03 mmol) was thenadded and the reaction refluxed for 3.5 hours. The reaction mixture waswashed with 1N HCl, dried (anhydrous MgSO₄) and the solvent removedunder reduced pressure to give 3.38 g of a clear oil. Purification ofthis oil on 300 g of silica gel (230-400 mesh) using hexane-methylenechloride as the eluent gave 2.71 g of a white crystalline solid.Recrystallization of this solid from diisopropyl ether-hexane then gavethe title compound as a white crystalline solid (2.02 g, 67%), mp 67-69C.

Elemental analysis for C₂₁ H₂₃ NO₅ Calc'd: C, 68.28; H, 6.28; N, 3.79Found: C, 68.61; H, 6.38; N, 3.88

EXAMPLE 50 2[[(Butylamino)carbonyloxy]-5-phenoxybenzoic acid methylester

In the same manner as described in Example 1, the title compound wasproduced from the intermediate prepared in paragraph 3 of the precedingexample as a white crystalline solid after purification bychromatography on silica gel (230-400 mesh) using methylene chloride asthe eluent (0.33 g, 58%), mp 53°-56° C.

Elemental analysis for C₁₉ H₂₁ NO₅ Calc'd: C, 66.46; H, 6.16; N, 4.08Found: C, 66.34; H, 6.21; N, 4.20

EXAMPLE 51 4-(1-Methylethyl)-1-piperidinecarboxylic acid 4-phenoxyphenylester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (3.02 g, 33%), mp 54°-55° C.

Elemental analysis for C₂₁ H₂₅ NO₃ Calc'd: C, 74.31; H, 7.42; N, 4.13Found: C, 74.03; H, 7.41; N, 4.00

EXAMPLE 52 8-Azaspiro[4,5]decan-8-carboxylic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (4.16 g, 44%), mp 53°-55° C.

Elemental analysis for C₂₂ H₂₅ NO₃ Calc'd: C, 75.19; H, 7.17; N, 3.99Found: C, 75.51; H, 7.36; N, 3.94

EXAMPLE 53 1,4-Piperidinedicarboxylic acid 4-dodecyl 1-(4-phenoxyphenyl)diester

Dodecyl alcohol (1.0 ml, 4.4 mmol) was added under a nitrogen atmosphereto a solution of the acid prepared in Example 46 (1.5 g, 4.4 mmol) and4-dimethylpyridine (0.54 g, 4.4 mmol) in 20 ml of methylene chloride atice bath temperature. Diisopropylcarbodiimide (650 μl, 4.4 mmol) in 5 mlof methylene chloride was then added dropwise over 15 minutes. After theaddition, the reaction was stirred at ice bath temperature for 1 hourand at room temperature for 3 hours. The reaction mixture was washedwith 1N HCl, 5% NaHCO₃, dried (anhydrous MgSO₄) and the solvent removedunder reduced pressure to give 2.46 g of residue. Purification of thisresidue by column chromatography on 250 g of silica gel (230-400 mesh)using methylene chloride as the eluent gave 1.80 g of a white solid.Recrystallization of this solid from hexane gave the title compound as awhite crystalline solid (1.13 g, 59% ), mp 35°-37° C.

Elemental analysis for C₃₁ H₄₃ NO₅ Calc'd: C, 73.05; H, 8.50; N, 2.75Found: C, 73.14; H, 8.79; N, 2.68

EXAMPLE 54 4-Methyl-1-piperidinecarboxylic acid 2-cyano-4-phenoxyphenylester

A mixture of the intermediate prepared in paragraph 1 of Example 49(14.95 g, 56.4 mmol), methyl iodide (17.6 ml, 283 mmol) and potassiumcarbonate (39 g, 282 mmol) in 150 ml of acetone was stirred under anitrogen atmosphere at room temperature overnight. The solid was removedby filtration and the flitrate concentrated under reduced pressure toremove the acetone. The residue was partitioned between methylenechloride and water. The organic layer was separated, dried (anhydrousMgSO₄) and the solvent removed under reduced pressure to give 15.35 g ofa yellow crystalline solid. Recrystallization of this solid from hexanegave 3-bromo-4-methoxybiphenyl ether as a white crystalline solid (10.58g, 67%), mp 50°-52° C.

Elemental analysis for C₁₃ H₁₁ BrO₂ Calc'd: C, 55.94; H, 3.97 Found: C,56.30; H, 3.97

n-Butyl lithium (24 ml of a 1.6 M solution in hexanes; 38.4 mmol) wasadded dropwise over 30 minutes under a nitrogen atmosphere to a solutionat -78° C. of 3-bromo-4-methoxybiphenyl ether (9.0 g, 32.2 mmol) in 250ml of dry THF. After the addition, the solution was stirred at -78° C.for 3 hours. N-Formylmorpholine (3.9 ml, 38.8 mmol) was then addeddropwise over 10 minutes. After the addition, the reaction was stirredat -78° C. for 30 minutes and then at room temperature overnight. Themixture was cooled to ice bath temperature and then 200 ml of 10% NH₄ Clwas added. The mixture was stirred at ice bath temperature for 30minutes. The reaction was partitioned between 1N HCl and EtOAc. Theorganic layer was separated, dried (anhydrous MgSO₄) and the solventremoved under reduced pressure to give 7.81 g of a yellow oil.Purification of this oil by HPLC (hexane-methylene chloride) gave 6.02 gof a light yellow crystalline solid. Recrystallization of this solidfrom diisopropyl etherhexane gave 2-methoxy-5-phenoxybenzaldehyde as awhite crystalline solid (4.80 g, 65%), mp 60°-61° C.

Elemental analysis for C₁₄ H₁₂ O₃ Calc'd: C, 73.67; H, 5.30 Found: C,73.83; H, 5.27

2-Methoxy-5-phenoxybenzaldehyde (4.5 g, 19.7 mmol) was dissolved in 60ml of warm methanol. Water (40 ml) was added to this solution followedby the addition of hydroxylamine hydrochloride (2.7 g, 38.9 mmol) andanhydrous sodium acetate (6.5 g, 79.2 mmol). This mixture was thenrefluxed for 4 hours. The reaction mixture was concentrated underreduced pressure to remove the methanol. The residue was partitionedwith ethyl acetate. The ethyl acetate layer was separated, washed fivetimes with water, dried (anhydrous MgSO₄) and the solvent removed underreduced pressure to give 2-methoxy-5-phenoxybenzaldehyde oxime as awhite crystalline solid (4.70 g, 98%), mp 95°-100° C.

Elemental analysis for C₁₄ H₁₃ NO₃ Calc'd: C, 69.13; H, 5.39; N, 5.76Found: C, 69.04; H, 5.35; N, 5.71

Thionyl chloride (11.9 ml, 163 mmol) was added under a nitrogenatmosphere to a suspension of 2-methoxy-5-phenoxybenzaldehyde oxime(3.96 g, 16.3 mmol) in 75 ml of benzene. There was a slight exotherm andthe mixture turned yellow. The reaction was heated to reflux temperatureover 1 hour and at reflux temperature for an additional hour. Thesolvent and excess thionyl chloride were removed under reduced pressureto give 2-methoxy-5-phenoxybenzonitrile as a light tan crystalline solid(3.66 g, 100% ), mp 88°-89° C.

Elemental analysis for C₁₄ H₁₁ NO₂ Calc'd: C, 74.65; H, 4.92; N, 6.22Found: C, 74.67; H, 4.78; N, 6.16

A round bottom flask containing 30 g of pyridinium hydrochloride was putunder a nitrogen atmosphere and submerged in an oil bath at 210° C.After the pyridinium hydrochloride melted2-methoxy-5-phenoxybenzonitrile (3.31 g, 14.7 mmol) was added and theresulting solution stirred at 210° C. (oil bath temperature) for 25minutes. After cooling to room temperature, the contents of the flasksolidified. The solid was partitioned between 1N HCl and ethyl acetate.The ethyl acetate layer was separated, dried (anhydrous MgSO₄) and thesolvent removed under reduced pressure to give 3.06 g of a browncrystalline solid. Purification of this solid by chromatography onsilica gel (230-400 mesh) using ethyl acetate-methylene chloride as aneluent gave 2-hydroxy-5-phenoxybenzonitrile as a white crystalline solid(2.56, 83%), mp 112°-114° C.

Elemental analysis for C₁₃ H₉ NO₂ Calc'd: C, 73.92; H, 4.30; N, 6.63Found: C, 74.23; H, 4.47; N, 6.60

4-Methyl-1-piperidinecarbonyl chloride (1.18 ml, 8.01 mmol) was addedunder a nitrogen atmosphere at room temperature to a solution of2-hydroxy-5-phenoxybenzonitrile (1.53 g, 7.26 mmol) and4-dimethylaminopyridine (0.976 g, 7.99 mmol) in 50 ml of benzene and theresulting solution refluxed for 1 hour. The reaction mixture was washedwith 1N HCl. The benzene layer was separated, dried (anhydrous MgSO₄)and the solvent removed under reduced pressure to give 2.57 g of a whitecrystalline solid. Rectystallization of this solid from diisopropylether-hexane gave the title compound as a white crystalline solid (1.59g, 65%), mp 54°-58° C.

Elemental analysis for C₂₀ H₂₀ N₂ O₃ Calc'd: C, 71.41; H, 5.99; N, 8.33Found: C, 71.67; H, 5.95; N, 8.38

EXAMPLE 55 4-Methyl-1-piperidinecarboxylic acid2-(hydroxycarbonyl-4-phenoxyphenyl ester

The ester produced in Example 49 (0.4519 g, 1.22 mmol) was dissolved in8 ml of THF and the solution put under a nitrogen atmosphere. Water (2ml) was added followed by the addition of 1.22 ml (1.22 mmol) of 1NNaOH. The solution was refluxed for 21 hours. The reaction waspartitioned between ethyl acetate and water. The organic layer wasseparated. The aqueous layer was acidified with 1N HCl and thenextracted three times with ethyl acetate. The ethyl acetate layer wasdried (anhydrous MgSO₄) and the solvent removed under reduced pressureto give 0.3452 g of a white solid. Recrystallization of this solid fromethyl acetate gave the title compound as a white crystalline solid(0.2094 g, 48%), mp 152° C. with decomposition.

Elemental analysis for C₂₀ H₂₁ NO₅ Calc'd: C, 67.59; H, 5.96; N, 3.94Found: C, 67.41; H, 5.82; N, 3.86

EXAMPLE 56 4-(Hydroxymethyl)-1-piperidinecarboxylic acid 4-phenoxyphenylester

The acid produced in Example 46 (2.0 g, 5.8 mmol) was dissolved in 20 mlof dry THF. The solution was put under a nitrogen atmosphere and cooledto ice bath temperature. Borane-THF complex (5.8 ml of a 1.0 M solutionin THF; 5.8 mmol) was added dropwise to the above solution and thereaction stirred at ice bath temperature for 2 hours. The reaction wasquenched with 1N HCl. The THF was removed under reduced pressure and theresidue partitioned between ethyl acetate and 1N HCl. The ethyl acetatelayer was separated, dried (anhydrous MgSO₄) and the solvent removedunder reduced pressure to give 1.84 g of a waxy solid. Purification ofthis solid by chromatography on silica gel (230-400 mesh) using ethylacetatemethylene chloride as an eluent gave the title compound as awhite solid (1.40 g, 74%), mp 71°-74° C.

Elemental analysis for C₁₉ H₂₁ NO₄ Calc'd: C, 69.71; H, 6.47; N, 4.28Found: C, 69.46; H, 6.51; N, 4.23

EXAMPLE 57 4-(Bromomethyl)-1-piperidinecarboxylic acid, 4-phenoxyphenylester

The ester produced in Example 56 (5.0 g, 15 mmol) and triphenylphosphine(4.0 g, 15 mmol) were dissolved in 100 ml of benzene and the resultingsolution put under a nitrogen atmosphere. N-Bromosuccinimide (2.7 g, 15mmol) was added in portions to the above solution and the reactionstirred at room temperature overnight. The solvent was removed underreduced pressure to give 12.3 g of a brown oil. Purification of this oilby chromatography on 600 g of silica gel (230-400 mesh) using ethylacetate-hexane as the eluent gave 4.52 g of a white solid.Recrystallization of this solid from diisopropyl ether gave the titlecompound as a white crystalline solid (4.12 g, 68%), mp 76°-78° C.

Elemental analysis for C₁₉ H₂₀ NO₃ Br Calc'd: C, 58.57; H, 5.17; N, 3.59Found: C, 58.50; H, 5.12; N, 3.43

EXAMPLE 58 4-Methyl-1-piperidinecarboxylic acid2-(dodecycloxycarbonyl)-4-phenoxyphenyl ester

The acid produced in Example 55 (2.0 g, 5.63 mmol) and4-dimethyaminopyridine (0.69 g, 5.67 mmol) were dissolved in 40 ml ofmethylene chloride and the solution put under a nitrogen atmosphere.Dodecyl alcohol (1.2 ml, 5.28 mmol) and diisopropylcarbodiimide (0.88ml, 5.62 mmol) were added in that order to the above solution and thereaction stirred at room temperature overnight. The reaction was washedwith 1N HCl, 5% NaHCO₃, dried (anhydrous MgSO₄) and the solvent removedunder reduced pressure. Purification of the residue (3.71 g) bychromatography on 400 g of silica gel (230-400 mesh) using methylenechloridehexane as the eluent gave the title compound as a white waxysolid (2.70 g, 97%), mp 37°-39° C.

Elemental analysis for C₃₂ H₄₅ NO₅ Calc'd: C, 73.39; H, 8.66; N, 2.68Found: C, 73.19; H, 8.36; N, 2.64

EXAMPLE 59 4-(Iodomethyl)-1-piperidinecarboxylic acid 4-phenoxyphenylester

A solution of the bromide produced in Example 57 (1.0 g, 2.56 mmol) andsodium iodide (3.8 g, 25.6 mmol) in 20 ml of acetone was refiuxed for 6hours and then stirred at room temperature overnight. The reactionmixture was partitioned between ethyl acetate and water. The organiclayer was separated, washed with water, dried (anhydrous MgSO₄) and thesolvent removed under reduced pressure to give 1.07 g of a white solid.Recrystallization of this solid from hexane gave the title compound as awhite crystalline solid (0.70 g, 64%), mp 106°-107° C.

Elemental analysis for C₁₉ H₂₀ NO₃ I Calc'd: C, 52.19; H, 4.61; N, 3.20Found: C, 52.50; H, 4.85; N, 3.12

EXAMPLE 60 4-(Diethylaminomethyl-1-piperidinecarboxylic acid4-phenoxyphenyl ester

A solution of the bromide (1.3 g, 3.3 mmol) produced in Example 57 in 13ml of diethylamine was refluxed under a nitrogen atmosphere for 6 days.The diethylamine was removed under reduced pressure to give 1.88 g of ayellow mushy solid. Purification of this solid by chromatography on 150g of silica gel (230-400 mesh) using hexane-ethyl acetate as the eluentgave 1.01 g of a yellow solid. Recrystallization of the solid fromhexane gave the title compound as a white crystalline solid (0.61 g,48%), mp 69°-70° C.

Elemental analysis for C₂₃ H₃₀ N₂ O₃ Calc'd: C, 72.22; H, 7.91; N, 7.32Found: C, 72.13; H, 8.23; N, 7.24

EXAMPLE 61 Triethyl1-[(4-phenoxyphenoxy)carbonyl]-4-piperidinemethanaminium iodide

A solution of the product of Example 61 (0.30 g, 0.78 mmol) and ethyliodide (2.8 ml, 39 mmol) in 30 ml of benzene was refluxed under anitrogen atmosphere for 48 hours. The solid formed was collected byfiltration, rinsed with benzene, hexane and then dried under high vacuumto give the title compound as a white solid (0.41 g, 96%), mp 151°-152°C.

Elemental analysis for C₂₅ H₃₅ N₂ O₃ I Calc'd: C, 55.76; H, 6.55; N,5.20 Found: C, 55.71; H, 6.77; N, 5.09

EXAMPLE 62 4-(Dihexylaminomethyl)-1-piperidinecarboxylic acid4-phenoxyphenyl ester

A solution of the bromide produced in Example 57 (3.0 g, 7.7 mmol) anddihexylamine (9.0 ml, 38 mmol) in 30 ml of toluene was refluxed under anitrogen atmosphere for 10 days. The solvent was removed under reducedpressure. Purification of the residue (9.88 g) by chromatography on 400g of silica gel (230-400 mesh) using hexane-ethyl acetate as the eluentgave the title compound as a light yellow solid (3.63 g, 96%), mp46°-47° C.

Elemental analysis for C₃₁ H₄₆ N₂ O₃ Calc'd: C, 75.26; H, 9.37; N, 5.66Found: C, 75.61; H, 9.74; N, 5.98

EXAMPLE 63 2-Methyl-1-piperidinecarboxylic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (1.57 g, 19%), mp 68°-70° C.

Elemental analysis for C₁₉ H₂₁ NO₃ Calc'd: C, 73.29; H, 6.80; N, 4.50Found: C, 73.18; H, 6.86; N, 4.61

EXAMPLE 64 Phenylcarbamic acid 4-phenoxyphenyl ester

In the same manner as described in Example 1, the title compound wasproduced as a white crystalline solid (4.80 g, 58%) after purificationby HPLC (hexane:ethyl acetate) and recrystallization from methylenechloride-isopropyl ether, mp 117°-118° C.

Elemental analysis for C₁₉ H₁₅ NO₃ Calc'd: C, 74.74; H, 4.95; N, 4.59Found: C, 74.59; H, 4.88; N, 4.38

EXAMPLE 65 Phenylmethylcarbamic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (4.26 g, 50%), mp 103°-104° C.

Elemental analysis for C₂₀ H₁₇ NO₃ Calc'd: C, 75.22; H, 5.36; N, 4.39Found: C, 75.48; H, 5.56; N, 4.29

EXAMPLE 66 Phenylethylcarbamic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white crystalline solid (3.80 g, 43%), mp 93°-94° C.

Elemental analysis for C₂₀ H₁₇ NO₃ Calc'd: C, 75.66; H, 5.75; N, 4.20Found: C, 76.00; H, 5.83; N, 4.35

EXAMPLE 67 (Z)-9-Octadecenylcarbamic acid 4-phenoxyphenyl ester

In the same manner as described in Example 2, the title compound wasproduced as a white waxy solid (6.90 g, 53%), mp 39°-43° C.

Elemental analysis for C₃₁ H₄₅ NO₃ Calc'd: C, 77.62; H, 9.46; N, 2.92Found: C, 77.62; H, 9.61; N, 3.01

In the same manner as described in Example 2, the following compoundscan be prepared from 4-phenoxyphenol and the appropriate amine.

(1-methyl-4-phenylbutyl)carbamic acid 4-phenoxyphenyl ester

methyl(4-phenylbutyl)carbamic acid 4-phenoxyphenyl ester

(11-phenylundecyl)carbamic acid 4-phenoxyphenyl ester

[4-(4-methylphenyl)butyl]carbamic acid 4-phenoxyphenyl ester

[4-(4-chlorophenyl)butyl]carbamic acid 4-phenoxyphenyl ester

[4-(4-methoxyphenyl)butyl]carbamic acid 4-phenoxyphenyl ester

[4-[4-(trifluoromethyl)phenyl]butyl]carbamic acid 4-phenoxyphenyl ester

[4-(3-cyanophenyl)butyl]carbamic acid 4-phenoxyphenyl ester

[4-(2-nitrophenyl)butyl]carbamic acid 4-phenoxyphenyl ester

[4-[(1,1'-biphenyl)-4-yl]butyl]carbamic acid 4-phenoxyphenyl ester

The ability of the compounds of this invention to inhibit the formationof cholesteryl esters and thereby interfere with and preventassimilation of cholesterol into the lymphatic system and ultimately theblood stream was established by incubating the compounds at 37° C. witha mixture of cholesterol and oleic acid in the presence of bufferedcholesterol esterase [(EC 3.1.1.13) Sigma Chemical Company, St. Louis,Mo., USA, No. C-1892, from bovine pancreas] and measuring the amount ofester formed, according to the procedure of Field, J. of Lipid Research,25 389 (1984). The concentration of test compound that inhibits one-halfof the ester formation (IC₅₀, μM) is given in the following Table.

The in vivo cholesterol absorption studies were conducted in normal ratsby oral administration of the compound being tested in propylene glycoland olive oil followed by oral administration of [4-¹⁴ C] cholesterol inpropylene glycol and olive oil, otherwise following the procedure ofCayen et al., J. Lipid Res. 20 162 (1979). The serum radioactivity wasmeasured at six hours after dosing. The results of this study arereported in the following Table, where available, as percent decreasecompared to control and in terms of the effective dose (ED₅₀) inhibitingfifty-percent of the absorption of the control animals.

                  TABLE                                                           ______________________________________                                                               In Vivo                                                Test Compound                                                                           In Vitro     Decrease in [.sup.14 C]                                Example   IC.sub.50 (μM)                                                                          Cholesterol Absorption                                 ______________________________________                                         1        2            82% decrease at 100 mg/kg                                                     ED.sub.50 = 24 mg/kg                                    2        0.13         82% decrease at 100 mg/kg                                                     ED.sub.50 = 24 mg/kg                                    3        16           70% decrease at 10 mg/kg                                                      ED.sub.50 = 6 mg/kg                                     4        5            89% decrease at 100 mg/kg                                                     ED.sub.50 = 13 mg/kg                                    5        33                                                                   6        55                                                                   7        85                                                                   8        0.2-0.06     90% decrease at 65 mg/kg                                                      ED.sub.50 = 10 mg/kg                                    9        >100         40% decrease at 100 mg/kg                              10        1.1          74% decrease at 65 mg/kg                                                      ED.sub.50 = 14 mg/kg                                   11        20                                                                  12        0.3          43% decrease at 65 mg/kg                               13        6.7                                                                 14        9.3                                                                 15        17.5         76% decrease at 100 mg/kg                              16        >100                                                                17        13.3                                                                18        16.5                                                                19        5.4                                                                 20        7.6          27% decrease at 65 mg/kg                               21        6.1                                                                 22        20% inhibition at                                                             30 μM;                                                                     plateau prior to                                                              reaching 1C.sub.50                                                  23        0.27         43% decrease at 65 mg/kg                               24        5.6                                                                 25        0.17         61% decrease at 65 mg/kg                               26        2.9                                                                 27        7.1                                                                 28        1.9                                                                 29        13                                                                  30        1.2          83% decrease at 65 mg/kg                               31        26                                                                  32        >100                                                                34        0.31         57% decrease at 65 mg/kg                               36        1.7                                                                 37        1.4                                                                 38        0.23         86% decrease at 50 mg/kg                               39        0.88         73% decrease at 50 mg/kg                               40        19                                                                  41        0.03         73% decrease at 50 mg/kg                               42        0.05         81% decrease at 50 mg/kg                               43        4.5          60% decrease at 50 mg/kg                               44        1.9          49% decrease at 50 mg/kg                               45        0.07         41% decrease at 10 mg/kg                               46        44           55% decrease at 100 mg/kg                              47        1.6          67% decrease at 20 mg/kg                               48        0.54         41% decrease at 50 mg/kg                               49        0.34         28% decrease at 50 mg/kg                               50        5.1                                                                 51        0.25         66% decrease at 20 mg/kg                               52        0.75         78% decrease at 50 mg/kg                               53        >100         44% decrease at 100 mg/kg                              54        0.44         36% decrease at 50 mg/kg                               55        31.3         16% decrease at 50 mg/kg                               56        2.1                                                                 57        0.08         87% decrease at 50 mg/kg                               58        0.34         37% decrease at 50 mg/kg                               59        0.27                                                                60         >100        49% decrease at 50 mg/kg                               61        >100         33% decrease at 50 mg/kg                               62        15                                                                  63        >100         68% decrease at 50 mg/kg                               67        626          49% decrease at 100 mg/kg                              ______________________________________                                    

Thus, the compounds of this invention axe useful in the treatment ofhigh serum cholesterol levels and associated disease states such ascoronary heart disease, atherosclerosis, familial hypercholesterolaemiahyperlipaemia and similar disease states. As such, they may beadministered to a hypercholesterolaemic patient, orally or parenterally,in an amount sufficient to reduce serum cholesterol concentrations tothe desired level. The dosage regimen for therapeutic use of theanti-hypercholesterolaemic agents of this invention will vary with theroute of administration, size and age of the person under treatment, aswell as the severity of the dysfunction under treatment. Therefore, thetreatment must be individualized for the patient under guidance of theattending physician.

The compounds of this invention may be administered by conventional oralor parenteral routes as solids, liquids or isotonic solutions.Conventional adjuvants known to the art may be combined with thecompounds to provide compositions and solutions for administrationpurposes, although it is considered desirable and feasible to use thecompounds neat or pure without additives other than for the purpose ofproviding suitable pharmaceutically acceptable solid or liquid dosageunits.

What is claimed is:
 1. A compound of the formula: ##STR15## in which R¹ is branched or straight chain, saturated or unsaturated alkyl of 4 to 20 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, 1-adamantyl, 2-adamantyl, 3-noradamantyl, 3-methyl-1-adamantyl, 1-fluorenyl, 9-fluorenyl, cycloalkylalkyl where the cycloalkyl moiety has 3 to 8 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, phenyl, substituted phenyl where the substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano or trifluoromethyl, phenylalkyl of 7 to 26 carbon atoms or substituted phenylalkyl, where the alkyl moiety is 1 to 20 carbon atoms and the substituent on the benzene ring is alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano, trifluoromethyl or phenyl;R² is hydrogen or alkyl of 1 to 6 carbon atoms; and R³, R⁴, R⁵ and R⁶ are, independently, hydrogen, branched or straight chain alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano, perhaloalkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 16 carbon atoms or hydroxycarbonyl.
 2. A compound of the formula: ##STR16## in which R¹ is cycloalkyl of 3 to 8 carbon atoms, 1-adamantyl, 2-adamantyl, 3-noradamantyl, 3-methyl-1-adamantyl, 1-fluorenyl, 9-fluorenyl, cycloalkylalkyl where the cycloalkyl moiety has 3 to 8 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, phenyl, substituted phenyl where the substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano or trifluoromethyl, phenylalkyl of 7 to 26 carbon atoms or substituted phenylalkyl, where the alkyl moiety is 1 to 20 carbon atoms and the substituent on the benzene ring is alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano, trifluoromethyl or phenyl;R² is hydrogen or alkyl of 1 to 6 carbon atoms; and R³, R⁴, R⁵ and R⁶ are, independently, hydrogen, branched or straight chain alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano, perhaloalkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 16 carbon atoms or hydroxycarbonyl.
 3. A compound of the forumla: ##STR17## in which R¹ is cycloalkyl of 4, 5, 6 or 7 carbon atoms, cycloalkylalkyl of 6 to 8 carbon atoms, phenylalkyl of 7 to 26 carbon atoms;R² is hydrogen, methyl or ethyl; and R³, R⁴, R⁵ and R⁶ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, halo, alkoxycarbonyl of 2 to 16 carbon atoms, hydroxycarbonyl, cyano or trihalomethyl.
 4. A compound of the formula: ##STR18## in which R¹ is branched or straight chain alkyl of 4 to 20 carbon atoms, cycloalkyl of 4, 5, 6 or 7 carbon atoms, cycloalkylalkyl of 6 to 8 carbon atoms, phenylalkyl of 7 to 26 carbon atoms;R² is hydrogen, methyl or ethyl; and R³, R⁴, R⁵ and R⁶ are, independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, halo, alkoxycarbonyl of 2 to 16 carbon atoms, hydroxycarbonyl, cyano or trihalomethyl.
 5. The compound of claim 1 which is butylcarbamic acid 4-phenoxyphenyl ester.
 6. The compound of claim 2 which is (4-phenylbutyl)carbamic acid 4-phenoxyphenyl ester.
 7. The compound of claim 1 which is (1,5-dimethylhexyl)carbamic acid 4-phenoxyphenyl ester.
 8. The compound of claim 1 which is octylcarbamic acid 4-phenoxyphenyl ester.
 9. The compound of claim 2 which is cyclohexylcarbamic acid 4-phenoxyphenyl ester.
 10. The compound of claim 2 which is cyclohexylmethylcarbamic acid 4-phenoxyphenyl ester.
 11. The compound of claim 2 which is tricyclo[3.3.1.1(3,7)dec-1-yl-carbamic acid 4-phenoxyphenyl ester.
 12. The compound of claim 1 which is (1,1,3,3-tetramethylbutyl)carbamic acid 4-phenoxyphenyl ester.
 13. The compound of claim 1 which is (1-ethylpentyl)carbamic acid 4-phenoxyphenyl ester.
 14. The compound of claim 1 which is (1,3-dimethylbutyl)carbamic acid 4-phenoxyphenyl ester.
 15. The compound of claim 1 which is butylcarbamic acid 4-(4-methylphenoxy)phenyl ester.
 16. The compound of claim 1 which is butylcarbamic acid 4-(4-nitrophenoxy)phenyl ester.
 17. The compound of claim 1 which is butylcarbamic acid 4-(4-chlorophenoxy)phenyl ester.
 18. The compound of claim 1 which is butylcarbamic acid 2,6-dimethyl-4-(4-methylphenoxy)phenyl ester.
 19. The compound of claim 1 which is (1,5-Dimethylhexyl)carbamic acid 4-(4-methylphenoxy)phenyl ester.
 20. The compound of claim 1 which is (1-methylhexyl)carbamic acid 4-phenoxyphenyl ester.
 21. The compound of claim 1 which is (1,5-dimethylhexyl)carbamic acid 4-(4-chlorophenoxy)phenyl ester.
 22. The compound of claim 1 which is butylcarbamic acid 2-fluoro-4-phenoxyphenyl ester.
 23. The compound of claim 1 which is butylcarbamic acid 4-(4-methoxyphenoxy)phenyl ester.
 24. The compound of claim 1 which is (1,5-dimethylhexyl)carbamic acid 4-(4-methoxyphenoxy)phenyl ester.
 25. The compound of claim 1 which is butylcarbamic acid 4-(4-tertbutylphenoxy)phenyl ester.
 26. The compound of claim 1 which is butylcarbamic acid 2-bromo-4-phenoxyphenyl ester.
 27. The compound of claim 1 which is (1,5-dimethylhexyl)carbamic acid 2-bromo-4-phenoxyphenyl ester.
 28. The compound of claim 1 which is hexylcarbamic acid 4-phenoxyphenyl ester.
 29. The compound of claim 1 which is (1,5-dimethylhexyl)carbamic acid 2-fluoro-4-phenoxyphenyl ester.
 30. The compound of claim 1 which is 2-[[(butylamino)carbonyl]oxy]-5-phenoxybenzoic acid methyl ester.
 31. The compound of claim 2 which is phenylcarbamic acid 4-phenoxyphenyl ester.
 32. The compound of claim 2 which is phenylmethylcarbamic acid 4-phenoxyphenyl ester.
 33. The compound of claim 2 which is phenylethylcarbamic acid 4-phenoxyphenyl ester.
 34. The compound of claim 1 which is (Z)-9-octadecenylcarbamic acid 4-phenoxyphenyl ester.
 35. A pharmaceutical composition comprising a cholesterol ester hydrolase inhibiting amount of a compound of the formula: ##STR19## in which R¹ is branched or straight chain, saturated or unsaturated alkyl of 4 to 20 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, 1-adamantyl, 2-adamantyl, 3-noradamantyl, 3-methyl-1-adamantyl, 1-fluorenyl, 9-fluorenyl, cycloalkylalkyl where the cycloalkyl moiety has 3 to 8 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, phenyl, substituted phenyl where the substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano or trifluoromethyl, phenylalkyl of 7 to 26 carbon atoms or substituted phenylalkyl, where the alkyl moiety is 1 to 20 carbon atoms and the substituent on the benzene ring is alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano, trifluoromethyl or phenyl;R² is hydrogen or alkyl of 1 to 6 carbon atoms; R³, R⁴, R⁵ and R⁶ are, independently, hydrogen, branched or straight chain alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano, perhaloalkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 16 carbon atoms or hydroxycarbonyl.
 36. The composition of claim 35 in which said compound is (4-phenylbutyl)carbamic acid 4-phenoxyphenyl ester.
 37. A process for reducing cholesterol absorption in a mammal in need of reduced serum cholesterol levels which comprises administering orally or parenterally, an amount of a compound of the following formula sufficient to reduce plasma cholesterol concentration: ##STR20## in which R¹ is branched or straight chain, saturated or unsaturated alkyl of 4 to 20 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, 1-adamantyl, 2-adamantyl, 3-noradamantyl, 3-methyl-1-adamantyl, 1-fluorenyl, 9-fluorenyl, cycloalkylalkyl where the cycloalkyl moiety has 3 to 8 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, phenyl, substituted phenyl where the substituents are alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano or trifluoromethyl, phenylalkyl of 7 to 26 carbon atoms or substituted phenylalkyl, where the alkyl moiety is 1 to 20 carbon atoms and the substituent on the benzene ring is alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano, trifluoromethyl or phenyl;R² is hydrogen or alkyl of 1 to 6 carbon atoms; and R³, R⁴, R⁵ and R⁶ are, independently, hydrogen, branched or straight chain alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, nitro, cyano, perhaloalkyl of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 16 carbon atoms or hydroxycarbonyl and a pharmaceutically acceptable carrier therefor.
 38. The process of claim 37 in which said compound is (4-phenylbutyl)carbamic acid 4-phenoxyphenyl ester. 